In addition to providing energy, lipids are also essential building blocks of our cell membranes. However, despite their importance, they remain poorly understood. A team from the University of Geneva (UNIGE) has revealed for the first time the secrets of their transport within cells. Each lipid uses a limited number of proteins to move from its place of production to its place of action. The team has also compiled an inventory of the proteins involved in the transport of hundreds of lipids. These findings, published in the journal Nature, provide a better picture of the functioning of our cells, as well as of many genetic and metabolic disorders, such as diabetes and Alzheimer's disease.

Lipids are often described as our organism's energy reserve, but this definition masks the diversity of their functions. They enable the absorption of some vitamins, are converted into hormones, and assemble into complex membranes. Their dysfunction is also linked to serious diseases such as Alzheimer's, where the lipid composition of nerve cells (neurons and astrocytes) is altered.

To be effective, lipids must be transported from where they are produced to where they are needed. Unlike proteins, they do not like water and therefore cannot move freely in the aqueous environment of the cell. They need transporters — lipid transfer proteins — that can protect them from direct exposure to the cell’s aqueous environment.

“While the general mechanism is well understood, the identity of the transporters responsible for each lipid remains largely unknown,” explains Anne-Claude Gavin, full professor in the Department of Cell Physiology and Metabolism at UNIGE Faculty of Medicine, responsible for this research initiated at the European Molecular Biology Laboratory (EMBL). “However, understanding how lipids move is essential to better treat the resulting disorders.”

Identifying pairs

Biologists at UNIGE brought together more than a hundred transfer proteins with hundreds of different lipids. The aim was to obtain the most comprehensive list possible of the ‘pairs’ formed between each protein and the lipids it can carry.

To do this, two experimental methods were combined. The first, carried out in a test tube, provides a highly controlled environment, while the second, which more closely corresponds to the inside of a cell, allows researchers to verify how these bonds are formed under near-real conditions. This is a world first on such a scale and at such a level of complexity. “The ‘‘couples’’ identified show that transfer proteins are not “buses” capable of transporting most lipids, but private chauffeurs with specific characteristics,” explains Anne-Claude Gavin.

Unravelling the secrets of lipids

This inventory represents a major advance in our understanding of lipid biology and opens up countless avenues for research. Although some of the principles that make lipid/protein coupling possible or impossible are known, the underlying mechanisms specific to each situation remain to be explored.

Scientists at UNIGE, in collaboration with Professor Nathalie Reuter of the University of Bergen in Norway, have been able to determine, using advanced mathematical models, how three transfer proteins recognise, among all lipids, those that they actually transport. "These discoveries could ultimately shed new light on the processes at work in many lipid metabolism disorders. This concerns rare genetic diseases such as Niemann-Pick syndrome, where the accumulation of fat in cells prevents many organs from functioning, but more commonly, metabolic disorders such as diabetes, or neurodegenerative diseases such as Alzheimer's disease," concludes the researcher.